Introduction: Discovery of endogenous cardiac progenitor cells (CPC) prompted intense research efforts in multiple experimental animal models and clinical trials for heart failure treatment. Our lab identified a fundamental difference in ploidy content between rodent (rat, mouse) CPCs possessing mononuclear tetraploid (4n) chromosome content versus large mammal (human, swine) CPCs with mononuclear diploid (2n) content. Ploidy differences raise provocative questions regarding translational applicability of myocardial regeneration in rodents as polyplodization often correlates with enhanced regenerative potential.
Hypothesis: Mononuclear chromatin duplication in CPCs improves regenerative capacity of the heart through higher stress resistance and overriding senescence cell-cycle arrest.
Methods and Results: Ploidy of cultured CPCs is consistent and stable ploidy content over increased passages with samples from eight humans, two swine strains, six mouse strains, and seven rat clonal lines as determined by karyotype, confocal microscope and flow cytometry analyses. In situ ploidy analysis of CPCs reveals diploid content in human tissue and a mixture of mononuclear diploid and tetraploid nuclei in mouse, confirmed using freshly isolated Lin- c-kit+ CPCs. Tetraploid nuclear phenotype of murine CPCs is markedly different from predominantly diploid murine c-kit+ cells in the heart or other tissues such as intestine and bone marrow. Higher ploidy content and reduction of diploid content concurrent with expansion of the CPC pool are evident in the border zone at four, seven and ten days post-infarction in adult FVB mice compared to age and gender matched non-injured hearts.
Conclusion: Tetraploid c-kit+ cells found within the rodent heart may contribute to species-specific characteristics of stem cells and myocardial regenerative capacity. Ongoing investigations focus upon identifying biological differences between diploid versus tetraploid CPCs and advantages of polyploid content for mediating myocardial regeneration.